Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection

Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity worldwide. There has been an extensive search for cardioprotective therapies to reduce myocardial ischemia-reperfusion (I/R) injury. Remote ischemic preconditioning (RIPC) is a phenomenon that relies on the body's endogenous protective modalities against I/R injury. In RIPC, non-lethal brief I/R of one organ or tissue confers protection against subsequent lethal I/R injury in an organ remote to the briefly ischemic organ or tissue. Initially it was believed to be limited to direct myocardial protection, however it soon became apparent that RIPC applied to other organs such as kidney, liver, intestine, skeletal muscle can reduce myocardial infarct size. Intriguing discoveries have been made in extending the concept of RIPC to other organs than the heart. Over the years, the underlying mechanisms of RIPC have been widely sought and discussed. The involvement of blood-borne factors as mediators of RIPC has been suggested by a number of research groups. The main purpose of this review article is to summarize the possible circulating mediators of RIPC, and recent studies to establish the clinical efficacy of these mediators in cardioprotection from lethal I/R injury.